A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3xe2x80x2 termini of the linear proviral DNA; covalent joining of the recessed 3xe2x80x2 OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The applicants additionally demonstrate that inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro and integrase as a component of the preintegration complex in HIV infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. The compounds of the present invention inhibit integrases of closely related lentiviruses such as HIV 2 and SIV, but not integrases from more distantly related retroviruses, for example RSV. These compounds do not inhibit binding or catalysis of other nucleic acid binding proteins, including enzymatic reactions such as those catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase II.
Zhao et al., (J. Med Chem. vol. 40, pp. 937-941 and 1186-1194 (1997)) describe hydrazide and arylamide HIV integrase inhibitors. Bis-catechols useful for inhibiting HIV integrase are described in LaFemina et al. (Antimicrobial Agents and Chemotherapy, vol. 39, no. 2, pp. 320-324, February 1995).
U.S. Pat. Nos. 4,377,258; 4,336,397; and 4,423,063 as well as Williams and Rooney (J. Med. Chem. vol 26, pp. 1196-1200, 1983) disclose 2,4-dioxo-4-substituted-1-butanoic acid derivatives useful intreating urinary tract calcium oxalate lithiasis. 4-substituted 2,4-dioxobutanoic acid compounds useful for inhibiting an influenza virus endonuclease are described in Tomassini et al. (Antimicrobial Agents and Chemotherapy, vol. 38, no. 12, pp. 2827-2837, December, 1994). 4-phenyl-4-oxo-butenoic acid derivatives are disclosed as useful as kynurenine-3-hydroxylase inhibitors for the prevention and/or treatment of neurodegenerative diseases in PCT/EP96/04517, which published as WO 97/17316 and in PCT/EP96/04518, which published as WO 97/17317.
Applicants have discovered that certain six-membered aromatic and heteroaromatic diketo acid derivatives are potent inhibitors of HIV integrase. These compounds are useful in the treatment of AIDS or HIV infection.
Compounds of formula I, as herein defined, are disclosed. These compounds are useful in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, either as compounds, pharmaceutically acceptable salts or hydrates (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV integrase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows: 
and tautomers and pharmaceutically acceptable salts thereof,
wherein:
A is a six-membered aromatic or heteroaromatic ring containing 0, 1, or 2 nitrogen heteroatoms substituted on carbon or nitrogen by R1, R2, R8, and R9;
optionally the aromatic ring may be fused with another ring system to form: 
R1 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94C1-5 alkyl,
(3) xe2x80x94C1-6 alkyl-OR7,
(4) xe2x80x94Oxe2x80x94C1-6 alkyl-OR7,
(5) xe2x80x94Oxe2x80x94C1-6 alkyl-SR7,
(6) xe2x80x94CF3 or xe2x80x94CH2CF3,
(7) -halo,
(8) xe2x80x94NO2,
(9) xe2x80x94C0-3 alkyl-N(R4)(R5),
(10) xe2x80x94R6,
(11) xe2x80x94C2-5 alkenyl-R3,
(12) xe2x80x94C2-5 alkynyl-R3,
(13) xe2x80x94Oxe2x80x94R6,
(14) xe2x80x94Oxe2x80x94C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with fluorine atoms,
(15) xe2x80x94Oxe2x80x94C1-6 alkyl-NHxe2x80x94C(O)xe2x80x94OR7;
(16) xe2x80x94Oxe2x80x94C2-6 alkyl-N(R4)(R5);
(17) xe2x80x94Sxe2x80x94C1-3 alkyl;
(18) xe2x80x94C(O)CH2C(O)C(O)OR7;
(19) xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2Oxe2x80x94R7; and
(20) xe2x80x94C(OH)(CH3)xe2x80x94CH2N(R4)(R5);
R2 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94R3,
(3) xe2x80x94C1-6 alkyl,
(4) xe2x80x94C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom,
(5) xe2x80x94C2-6 alkenyl,
(6) xe2x80x94Oxe2x80x94R6,
(7) xe2x80x94Oxe2x80x94C1-6 alkyl-OR6,
(8) xe2x80x94Oxe2x80x94C1-6 alkyl-SR6,
(9) xe2x80x94S(O)nxe2x80x94R6,
(10) xe2x80x94C1-6 alkyl (OR6)(R4),
(11) xe2x80x94C0-6 alkyl-N(R4)(R6),
(12) xe2x80x94C1-6 alkyl S(O)nxe2x80x94R6,
(13) xe2x80x94C0-6 alkyl C(O)R6,
(14) xe2x80x94C0-6 alkyl C(O)CH2xe2x80x94C(O)xe2x80x94OH,
(15) xe2x80x94C1-6 alkyl C(S)xe2x80x94R6,
(16) xe2x80x94C1-6 alkyl NR4C(O)xe2x80x94R6,
(17) xe2x80x94C1-6 alkyl-C(O)N(R4)(R5), and
(18) xe2x80x94CH2(OR7)xe2x80x94R6;
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on nitrogen or carbon by 1 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94C1-6 alkyl,
(f) xe2x80x94CN,
(g) hydroxy,
(h) phenyloxy,
(i) xe2x80x94C0-6 alkyl-N(R7)2, 
(k) oxo, and
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O,
(h) benzyl, and
(i) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo,
(b) halogen,
(c) C1-6 alkyl,
(d) C1-6 alkyloxy-,
(e) xe2x80x94CF3,
(f) xe2x80x94OCF3,
(g) xe2x80x94CN, and
(h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen,
(b) xe2x80x94C1-6 alkyl,
(c) xe2x80x94C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94CF3,
(f) xe2x80x94CN, and
(g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O, and
(h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O, and
(h) hydroxy; and
(7) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O, and
(h) hydroxy; and
each R4 is independently selected from:
(1) xe2x80x94H,
(2) xe2x80x94C1-4 alkyl,
(3) xe2x80x94CF3,
(4) xe2x80x94R3,
(5) xe2x80x94C2-3 alkenyl,
(6) xe2x80x94C1-3 alkyl-R3,
(7) xe2x80x94C2-3 alkenyl-R3,
(8) xe2x80x94S(O)nxe2x80x94R3, and
(9) xe2x80x94C(O)xe2x80x94R3;
each R5 is independently selected from:
(1) xe2x80x94H,
(2) xe2x80x94C1-3 alkyl,
(3) xe2x80x94CF3,
(4) xe2x80x94R3,
(5) xe2x80x94C2-3 alkenyl,
(6) xe2x80x94C1-3 alkyl-R3,
(7) xe2x80x94C2-3 alkenyl-R3,
(8) xe2x80x94S(O)nxe2x80x94R3,
(9) xe2x80x94C(O)xe2x80x94R3,
(10) xe2x80x94C(O)OR4, and
(11) xe2x80x94C(O)C(O)OH;
each R6 is independently selected from:
(1) xe2x80x94C1-3 alkyl-R3, and
(2) xe2x80x94R3;
each R7 is independently selected from:
(1) xe2x80x94H, and
(2) xe2x80x94C1-6 alkyl;
R8 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94Oxe2x80x94C1-6 alkyl and
(3) C1-6 alkyl;
R9 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94Oxe2x80x94C1-3 alkyl,
(3) xe2x80x94OH, and
(4) oxo; and
each n is independently selected from 0, 1 and 2.
Also provided for by the present invention are compounds of structural formula (I) wherein:
when A is phenyl:
(1) R1 is not R6 para to the dioxobutyric acid/ester moiety; and
(2) R2 is not selected from:
(a) phenyl para to the dioxobutyric acid/ester moiety,
(b) substituted phenyl para to the dioxobutyric acid/ester moiety,
(c) xe2x80x94C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety, and
(d) substituted xe2x80x94C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety; and
(3) at least one of R1, R2, and R8 is not:
(a) xe2x80x94H,
(b) C1-6 alkyl, or
(c) R3 wherein R3 is cycloalkyl; and
(4) and when R2 is S(O)nR6, and R6 is CH2xe2x80x94R3 or R3, then R3 is not unsubstituted phenyl.
Also provided for by the present invention are compounds of formula (I) wherein:
WHEN A is phenyl and R1 is:
(a) H,
(b) C1-5 alkyl,
(c) halo,
(d) NO2,
(e) R6 when R6 is CH2R3 or R3 and when R3 is unsubstituted phenyl,
(f) xe2x80x94Oxe2x80x94C1-6 alkyl, or
(g) xe2x80x94SC1-3 alkyl;
THEN R2 is not selected from:
(a) H,
(b) R3 when R3 is unsubstituted phenyl,
(c) C1-6 alkyl,
(d) CH2R3 when R3 is unsubstituted phenyl, and
(e) SOR6 when R6 is CH2R3 or R3 and when R3 is unsubstituted phenyl.
Also provided for by the present invention are compounds of formula (I) wherein at least one of R1, R2, R8 and R9 is not hydrogen.
Also provided for by the present invention are compounds of formula (I) wherein: when A is a fused ring system, the six-membered aromatic ring is substituted by the dioxobutyric acid/ester moiety
Applicants hereby incorporate by reference the disclosure of U.S. provisional application Serial No. 60/087,820, filed Jun. 3, 1998.
Also provided are compounds of formula Ia, which are defined as follows: 
and tautomers and pharmaceutically acceptable salts thereof,
wherein:
A is a six-membered aromatic or heteroaromatic ring containing 0, 1, or 2 heteroatoms selected from nitrogen and substituted on carbon or nitrogen by R1, R2 and R8; the aromatic or heteroaromatic ring may optionally be fused with a 5- or 6-membered aromatic or heteroaromatic ring to form a fused ring system, provided that when A is a fused ring system, the six-membered aromatic or heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety;
optionally the aromatic or heteroaromatic ring may be fused with another ring system to form: 
R1 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94C1-5 alkyl,
(3) xe2x80x94CF3,
(4) -halo,
(5) xe2x80x94NO2,
(6) xe2x80x94N(R4)(R5),
(7) xe2x80x94R6,
(8) xe2x80x94C2-5 alkenyl-R3,
(9) xe2x80x94C2-5 alkynyl-R3,
(10) xe2x80x94Oxe2x80x94R6,
(11) xe2x80x94Oxe2x80x94C1-6 alkyl, and
(12) xe2x80x94C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94R3,
(3) xe2x80x94C1-6 alkyl,
(4) xe2x80x94C1-6 alkyl substituted with R3,
(5) xe2x80x94Oxe2x80x94R6,
(6) xe2x80x94Oxe2x80x94C1-6 alkyl-OR6,
(7) xe2x80x94S(O)nxe2x80x94R6,
(8) xe2x80x94C1-6 alkyl (OR6)(R4),
(9) xe2x80x94C0-6 alkyl-N(R4)(R6),
(10) xe2x80x94C1-6 alkyl S(O)nxe2x80x94R6,
(11) xe2x80x94C1-6 alkyl C(O)xe2x80x94R6,
(12) xe2x80x94C1-6 alkyl C(S)xe2x80x94R6,
(13) xe2x80x94C1-6 alkyl NR4C(O)xe2x80x94R6, and
(14) xe2x80x94C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) xe2x80x94CF3,
(f) xe2x80x94OCF3,
(g) xe2x80x94CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O,
(h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo,
(b) halogen,
(c) C1-6 alkyl,
(d) C1-6 alkyloxy-,
(e) xe2x80x94CF3,
(f) xe2x80x94OCF3,
(g) xe2x80x94CN, and
(h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen,
(b) xe2x80x94C1-6 alkyl,
(c) xe2x80x94C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN, and
(g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O,
(h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O,
(h) hydroxy;
each R4 is independently selected from:
(1) xe2x80x94H,
(2) xe2x80x94C1-3 alkyl,
(3) xe2x80x94CF3,
(4) xe2x80x94R3,
(5) xe2x80x94C2-3 alkenyl,
(6) xe2x80x94C1-3 alkyl-R3,
(7) xe2x80x94C2-3 alkenyl-R3,
(8) xe2x80x94S(O)nxe2x80x94R3, and
(9) xe2x80x94C(O)xe2x80x94R3;
each R5 is independently selected from:
(1) xe2x80x94H,
(2) xe2x80x94C1-3 alkyl,
(3) xe2x80x94CF3,
(4) xe2x80x94R3,
(5) xe2x80x94C2-3 alkenyl,
(6) xe2x80x94C1-3 alkyl-R3,
(7) xe2x80x94C2-3 alkenyl-R3,
(8) xe2x80x94S(O)nxe2x80x94R3, and
(9) xe2x80x94C(O)xe2x80x94R3;
each R6 is independently selected from:
(1) xe2x80x94C1-3 alkyl-R3, and
(2) xe2x80x94R3;
R7 is selected from:
(1) xe2x80x94H, and
(2) C1-6 alkyl;
R8 is selected from:.
(1) xe2x80x94H,
(2) xe2x80x94Oxe2x80x94C1-6 alkyl, and
(3) C1-6 alkyl; and
each n is independently selected from 0, 1 and 2.
Also provided by the present invention are compounds of structural formula (Ia) wherein:
when A is phenyl,
(1) R1 is not:
(a) phenyl para to the dioxobutyric acid/ester moiety,
(b) substituted phenyl para to the dioxobutyric acid/ester moiety,
(c) C1-3 alkyl phenyl para to the dioxobutyric acid/ester moiety, or
(d) substituted xe2x80x94C1-3 alkyl phenyl para to the dioxobutyric acid/ester moiety; and
(2) R2 is not selected from:
(a) phenyl para to the dioxobutyric acid/ester moiety,
(b) substituted phenyl para to the dioxobutyric acid/ester moiety,
(c) xe2x80x94C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety, and
(d) substituted xe2x80x94C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety; and
(3) at least one of R1, R2, and R8 is not:
(a) xe2x80x94H,
(b) C1-6 alkyl, or
(c) R3 wherein R3 is cycloalkyl; and
(4) and when R1 or R2 is S(O)nR6, R6 is R3.
Particular compounds of structural formula Ia include:
(1) 3-biphenyl-4-yl-2,4-dioxobutanoic acid,
(2) 4-(3,5-bis-benzyloxyphenyl)-2-hydroxy-4-oxo-but-2-enoic acid,
(3) 4-[3-(3,4-difluorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid,
(4) 4-[3-(4-methylbenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid,
(5) 4-(3-benzyloxy-5-methoxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid,
(6) 4-(3-benzyloxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid,
(7) 4-[3-(4-chlorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid,
(8) 4-[3-(3,4-dichlorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid,
(9) 4-[3-(4-fluorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid,
(10) 4-[3-(3-chlorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid,
(11) 4-[3-benzyloxy-5-(6-tert-butoxycarbonylaminohexyloxy)phenyl]-2-hydroxy-4-oxobut-2-enoic acid,
(12) 4-(3-(4-methoxybenzyloxy)phenyl)-4-oxo-2-butenoic acid,
(13) 4-(3-benzyloxy-5-hydroxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid,
(14) 4-(3-(1-phenylethoxy)phenyl)-4-oxo-2-butenoic acid,
(15) 4-[3-benzyloxy-5-(6-[5-(2-oxohexahydrothieno[3,4-d]imidazol-4-yl)pentanoylamino]hexyloxy)-phenyl]-2-hydroxy-4-oxobut-2-enoic acid,
(16) 4-[3-(6-aminohexyloxy)-5-benzyloxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid,
(17) 4-(3-dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid,
(18) 4-(3-chloro-phenyl)-2,4-dioxo-butanoic acid, and
(19) 4-(3-benzyl-phenyl)-2,4-dioxo-butanoic acid,
(20) 4-(4-dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid,
(21) 4-(4-benzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid,
(22) 4-(2-benzyloxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid,
(23) 4-naphthalen-1-yl-2,4-dioxobutanoic acid, and
(24) 4-naphthalen-2-yl-2,4-dioxobutanoic acid,
(25) 4-(6-benzyloxy-2-oxo-1,2-dihydropyridin-4-yl)-2-hydroxy-4-oxobut-2-enoic acid, and
(26) 4-(2,6-Bis benzyloxypyridin-4-yl)-2,4-dioxobutanoic acid,
(27) 4-[1-(4-fluorobenzyl)-5-indolyl]-2-hydroxy-4-oxo-2-butenoic acid,
(28) 4-[1-(4-fluorobenzyl)-4-indolyl]-2-hydroxy-4-oxo-2-butenoic acid,
(29) 4-(4-benzyloxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid,
(30) 4-[1-(4-fluorobenzyl)-6-indolyl]-2-hydroxy-4-oxo-2-butenoic acid, and
(31) 4-biphenyl-4-yl-2,4-dioxobutanoic acid,
and tautomers and pharmaceutically acceptable salts thereof.
Particular compounds of structural formula (I) include:
(1) 4-(3,5-Bis-benzyloxy-phenyl)-2,4-dioxobutanoic acid,
(2) 4-[3-Benzyloxy-5-(2-morpholin-4-yl-ethoxy)-phenyl]-2,4-dioxobutanoic acid,
(3) 4-[3-Benzyloxy-5-(6-tert-butoxycarbonylamino-hexyloxy)phenyl]-2,4-dioxobutanoic acid,
(4) 4-(3-Benzylphenyl)-2,4-dioxobutanoic acid,
(5) 4-[3-(2-chlorobenzyl)phenyl]-2,4-dioxobutanoic acid,
(6) 4-(4-Dibenzylaminophenyl)-2,4-dioxobutanoic acid,
(7) 4-(3-Dibenzylaminophenyl)-2,4-dioxobutanoic acid,
(8) 1-(3-benzyloxy-5-methoxyphenyl)-2,4-dioxobutanoic acid,
(9) 1-(3-Benzyloxyphenyl)-2,4-dioxobutanoic acid,
(10) 1-(2-Benzyloxyphenyl)-2,4-dioxobutanoic acid,
(11) 1-[3-(4-Fluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid,
(12) 1-[3-(3,4-Difluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid,
(13) 4-[3-(5-methyl-thiophen-2-ylmethyl)-phenyl]-2,4-dioxobutyric acid,
(14) 4-{3-[(methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxobutyric acid,
(15) 4-(3-benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid,
(16) 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid,
(17) 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid,
(18) 4-[3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(19) 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxobutyric acid,
(20) 4-(5-Benzyl-2-isopropoxyphenyl)-2,4-dioxobutyric acid,
(21) 4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid,
(22) 4-[5-Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid,
(23) 4-(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid,
(24) 4-(5-Benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid,
(25) 4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4-dioxobutyric acid,
(26) 4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxobutyric acid,
(27) 4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric acid,
(28) 4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylphenyl)-2,4-dioxobutyric acid,
(29) 4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid,
(30) 4-[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl) phenyl]-2,4-dioxo-butyric acid,
(31) 4-(5-benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyric acid,
(32) 4-(3-Benzyl-4-methoxyphenyl)-2,4-dioxobutyric acid,
(33) 4-(5-Benzyl-2-methoxyphenyl)-2,4-dioxobutyric acid,
(34) 4-(3-Benzyl-4-fluorophenyl)-2,4-dioxobutyric acid,
(35) 4-(3-Benzyl-4-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid,
(36) 4-[5-(2-Methylbenzyl)-2,3-dimethoxyphenyl]-2,4-dioxobutyric acid,
(37) 2,4-Dioxo-4-(3-pyridin-2-ylmethylphenyl)butyric acid,
(38) 4-(5-Benzyl-3-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid,
(39) 4-(5-Benzyl-3-methoxyphenyl)-2,4-dioxobutyric acid,
(40) 4-(5-Benzyl-2-benzyloxy-3-methoxyphenyl)-2,4-dioxobutyric acid,
(41) 4-[5-(3-Methylbenzyl)-2,3-dimethoxyphenyl]-2,4-dioxobutyric acid,
(42) 4-(5-Benzyl-3-benzyloxyphenyl)-2,4-dioxobutyric acid,
(43) 4-[5-Benzyl-2-(2-hydroxy)ethoxyphenyl]-2,4- dioxo-2-butanoic acid,
(44) 2,4-Dioxo-4-(3-pyridin-3-ylmethylphenyl)butyric acid,
(45) 4-[3-(3-Methyl-pyridin-2-ylmethyl)phenyl]-2,4-dioxo-butyric acid,
(46) 4-(5-Benzyl-2-methylsulfanylphenyl)-2,4-dioxobutyric acid,
(47) 4-(5-Benzyl-3-N-morpholinophenyl)-2,4-dioxobutyric acid,
(48) 4-(8-Benzyl-4-methyl-3,4-dihydro-2h-benzo[1,4]oxazin-6-yl)-2,4-dioxobutyric acid,
(49) 4-[5-(2-Chlorobenzyl)-3-N,N-dimethylaminophenyl]-2,4-dioxobutyric acid,
(50) 4-[5-(3-Chlorobenzyl)-3-N,N-dimethylaminophenyl]-2,4-dioxobutyric acid,
(51) 4-(5-Benzyl-2,3,4-trimethoxyphenyl)-2,4-dioxobutyric acid,
(52) 4-(6-Benzylbenzo[1,3]dioxol-4-yl)-2,4-dioxobutyric acid,
(53) 4-[3-Benzyl-5-(morpholine-4-carbonyl)phenyl]-2,4-dioxobutyric acid,
(54) 4-(3-Benzyl-5-pyridine-2-ylmethylphenyl)-2,4-dioxobutyric acid,
(55) 4-[3-Benzyl-5-(morpholinomethyl)phenyl]-2,4-dioxobutyric acid,
(56) 4-(3-Benzyl-5-pyridine-3-ylmethylphenyl)-2,4-dioxobutyric acid,
(57) 4-[3-Benzyl-5-(2-dimethylamino-1-hydroxy-1-methylethyl)phenyl]-2,4-dioxobutyric acid,
(58) 4-(5-Benzyl-2-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid,
(59) 4-(5-Benzyl-2-fluorophenyl)-2,4-dioxobutyric acid,
(60) 4-(5-Benzyl-3-hydroxymethyl-2-methoxyphenyl)-2,4-dioxobutyric acid,
(61) 4-[5-Benzyl-2-(pyrazin-2-yloxy)phenyl]-2,4-dioxobutyric acid,
(62) 4-[3-Benzyl-5-(2-oxopiperidin-1-ylmethyl)phenyl]-2,4-dioxobutyric acid,
(63) 4-[5-Benzyl-2-methoxy-3-(morpholinomethyl)phenyl]-2,4-dioxobutyric acid,
(64) 4-[3-(2-Chlorobenzyl)-5-pyridin-2-ylmethylphenyl]-2,4-dioxobutyric acid,
(65) 4-[5-Benzyl-2-methoxy-3-(4-methylpiperazin-1-ylmethyl)phenyl]-2,4-dioxobutyric acid,
(66) 4-(5-Benzyl-2-methoxymethylphenyl)-2,4-dioxobutyric acid,
(67) 4-[3-(2-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid,
(68) 4-[3-(4-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid,
(69) 4-[3-(3-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid,
(70) 4-[5-Benzyl-2-methoxy-3-(tert-butylcarbamoyl)phenyl]-2,4-dioxobutyric acid,
(71) 4-(3-Benzyl-5-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid,
(72) 4-[5-Benzyl-3-(Nxe2x80x2-methyl-N-piperazinyl)phenyl]-2,4-dioxobutyric acid,
(73) 4-(3-Benzyl-5-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid,
(74) 4-(6-Benzyl-3-oxo-3,4-dihydro-2xe2x80x94H-benzo[1,4]oxazin-8-yl)-2,4-dioxobutyric acid,
(75) 4-[5-Benzyl-2-(pyrimidin-2-yloxy)phenyl]-2,4-dioxobutyric acid,
(76) 4-(5-Benzyl-3-amino-2-methoxyphenyl)-2,4-dioxobutyric acid,
(77) 4-(5-Benzyl-2-ethoxyphenyl)-2,4-dioxobutyric acid,
(78) 4-[5-Benzyl-2-(2-morpholin-4-yl-ethoxy)phenyl]-2,4-dioxobutyric acid,
(79) 4-(5-Benzyl-2-trifluoroethoxyphenyl)-2,4-dioxobutyric acid,
(80) 4-(5-Benzyl-2-cyclobutyloxyphenyl)-2,4-dioxobutyric acid,
(81) 4-(5-Benzyl-2-cyclopentyloxyphenyl)-2,4-dioxobutyric acid,
(82) 4-(3-Benzyl-5-tetrazol-2-ylmethylphenyl)-2,4-dioxobutyric acid,
(83) 4-(5-Benzyl-2,3-diisopropoxyphenyl)-2,4-dioxobutyric acid,
(84) 4-(5-Benzyl-2-isopropoxy-3-N-methylaminophenyl)-2,4-dioxobutyric acid,
(85) 4-(5-Benzyl-2-isopropoxy-3-N,N-dimethylaminophenyl)-2,4-dioxo-butyric acid,
(86) 4-[5-Benzyl-2-isopropoxy-3-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid,
(87) 4-[5-Benzyl-2-isopropoxy-3-(morpholinomethyl)phenyl]-2,4-dioxo-butyric acid,
(88) 4-(5-Benzyl-2-isopropoxy-3-N,N-dimethylaminomethylphenyl)-2,4-dioxo-butyric acid,
(89) 4-(7-Benzylbenzo[1,3]dioxol-5-yl)-2-hydroxy-4-oxobut-2-enoic acid,
(90) 2xe2x80x94Hydroxy-4-oxo-4-(3-phenylindan-5-yl)but-2-enoic acid,
(91) 4-(Dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid,
(92) 3-(3-Benzyl-5-carboxyacetylphenyl)-3-oxopropionic acid,
(93) 4-(4-Dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid,
(94) 4-(5-Benzyl-3-methoxy-2-methylthioethoxyphenyl)-2,4-dioxobutyric acid,
(95) 4-(7-Benzyl-2,3-dihydrobenzo[1,4]dioxin-5-yl)-2,4-dioxobutyric acid,
(96) (+/xe2x88x92) 4-(8-Benzyl-3-hydroxy-3,4-dihydro-2H-benzo[B][1,4]dioxepin-6-yl)-2,4-dioxobutyric acid,
(97) 4-(2,3-Dimethoxy-5-pent-4-enylphenyl)-2,4-dioxobutyric acid,
(98) 4-(5-Cyclopropylmethyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid,
(99) (6-Benzyloxy-1-oxo-indan-2-ylidene)-hydroxyacetic acid,
(100) 4-(5-Benzyl-2-isopropoxy-3-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid,
(101) 4-(5-Benzyl-2-isopropoxy-3-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid,
(102) 4-[5-Benzyl-2-(3-N,N-dimethylaminopropoxy)-3-methoxyphenyl]-2,4-dioxobutyric acid,
(103) 4-[3-(Phenyldifluoromethyl)phenyl]-2,4-dioxobutyric acid,
(104) 4-(5-Benzyl-2-cyclopropyloxyphenyl)-2,4-dioxobutyric acid,
(105) 4-[5-Benzyl-2-isopropoxy-3-(1-piperidinylmethyl)phenyl]-2,4-dioxo-butyric acid,
(106) 4-[5-Benzyl-2-(2-dimethylamino-1-methylethoxy)phenyl]-2,4-dioxo-butyric acid,
(107) 4-[5-Benzyl-2-(1-methylpiperidin-4-yloxy)phenyl]-2,4-dioxo-butyric acid,
(108) 4-[3-Benzyl-5-(4-benzylpiperazin-1-yl)phenyl]-2,4-dioxo-butyric acid,
(109) 4-[5-Benzyl-2-isopropoxy-3-(pyridin-2-ylaminomethyl)phenyl]-2,4-dioxo-butyric acid,
(110) 4-[1-(2,6-Difluorobenzyl)-1H-indol-6-yl]-2,4-dioxobutyric acid,
(111) 4-(1-Benzyl-1H-indol-6-yl)-2,4-dioxobutyric acid,
(112) 1-[1-(4-Fluorobenzyl)-6-indolyl]-2,4-dioxobutanoic acid,
(113) 1-[1-(4-Fluorobenzyl)-4-indolyl]-2,4-dioxobutanoic acid,
(114) 4-[3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(115) 2,4-Dioxo-4-[3-(2,6-difluoro-benzyl)-phenyl]-butyric acid,
(116) 2,4-Dioxo-4-[3-(2-4-6-trifluoro-benzyl)-phenyl]-butyric acid,
(117) 2,4-Dioxo-4-[3-(2-fluoro-3-chloro-benzyl)-phenyl]-butyric acid,
(118) 2,4-Dioxo-4-[3-(2-methyl-4-fluoro-benzyl)-phenyl]-butyric acid,
(119) 4-[3-(2,3-Dichloro-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(120) 4-[3-(2-Chloro-3-methylbenzyl)phenyl]-2,4-dioxobutyric acid,
(121) 2,4-Dioxo-4-[3-(2,6-dichloro-benzyl)-phenyl]-butyric acid,
(122) 2,4-Dioxo-4-[3-(2,3,4,5,6-penta-fluoro-benzyl)-phenyl]-butyric acid,
(123) 4-[3-(2-Fluorobenzyl)phenyl]-2,4-dioxobutyric acid,
(124) 2,4-Dioxo-4-[3-(2-chloro-4-fluoro-benzyl)-phenyl]-butyric acid,
(125) 4-[3-(2-Methylbenzyl)phenyl]-2,4-dioxobutyric acid,
(126) 2,4-Dioxo-4-[3-(2-methoxybenzyl)phenyl]butyric acid,
(127) 4-[3-(2-Chlorobenzyl)phenyl]-2,4-dioxobutyric acid,
(128) 4-[3-(2-Bromobenzyl)phenyl]-2,4-dioxobutyric acid,
(129) 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxobutyric acid,
(130) 4-[3-(3-Chloro-2-methyl-benzyl)phenyl]-2,4-dioxobutyric acid,
(131) 4-[3-(2,3-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(132) 4-(3,5-Dibenzylphenyl)-2,4-dioxo-butyric acid,
(133) 2,4-Dioxo-4-[3-(2-trifluoromethylbenzyl)phenyl]butyric acid,
(134) 4-[3-(4-Fluorobenzyl)phenyl]-2,4-dioxobutyric acid,
(135) 4-[3-(3-Chlorobenzyl)phenyl]-2,4-dioxobutyric acid,
(136) 2,4-Dioxo-4-[3-(2-bromo-3-chloro-benzyl)-phenyl]-butyric acid,
(137) 4-(3-Benzylphenyl)-2,4-dioxo-butyric acid,
(138) 4-[3-(2-Fluoro-3-methyl-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(139) 4-[3-(3-Chloro-4-fluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(140) 2,4-Dioxo-4-[3-(2-bromo-4-fluoro-benzyl)-phenyl]-butyric acid,
(141) 4-[3-(3-Bromobenzyl)phenyl]-2,4-dioxobutyric acid,
(142) 4-[3-(2,5-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(143) 4-[3-(5-Chloro-2-fluoro-benzyl)phenyl]-2,4-dioxobutyric acid,
(144) 4-[3-(3-Methylbenzyl)phenyl]-2,4-dioxobutyric acid,
(145) 4-(3-Benzyl-4-methyl-phenyl)-2,4-dioxo-butyric acid,
(146) 4-[3-(3,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(147) 4-[3-(2,5-Dichloro-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(148) 4-[3-(2-Chloro-6-methyl-benzyl)phenyl]-2,4-dioxobutyric acid,
(149) 2,4-Dioxo-4-[3-(2-trifluoromethyl-4-chloro-benzyl)-phenyl]-butyric acid,
(150) 4-[3-(2-Bromo-5-chloro-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(151) 4-(3-Naphthalen-1-ylmethyl-phenyl)-2,4-dioxo-butyric acid,
(152) 2,4-Dioxo-4-[3-(3-fluorobenzyl)phenyl]butyric acid,
(153) 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid,
(154) 2,4-Dioxo-4-[3-(1-phenylethyl)phenyl]butyric acid,
(155) 4-(3-Benzyl-4,5-dimethylphenyl)-2,4-dioxo-butyric acid,
(156) 2,4-Dioxo-4-[3-(3-methoxybenzyl)phenyl]butyric acid,
(157) 4-[3-(5-Methyl-thiophen-2-ylmethyl)phenyl]-2,4-dioxo-butyric acid,
(158) 4-[3-(5-Chloro-thiophen-2-ylmethyl)phenyl]-2,4-dioxo-butyric acid,
(159) 4-(3-Benzyl-5-methylphenyl)-2,4-dioxo-butyric acid,
(160) 4-[3-(2-Cyanobenzyl)phenyl]-2,4-dioxo-butyric acid,
(161) 4-[3-Benzylphenyl]-2,4-dioxobutyric acid,
(162) 4-[3-(3,5-Dichloro-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(163) 4-(5-Benzyl-2,4-dimethylphenyl)-2,4-dioxo-butyric acid,
(164) 4-(5-Benzyl-2-methylphenyl)-2,4-dioxo-butyric acid,
(165) 4-(3-Cyclohexylmethyl-phenyl)-2,4-dioxo-butyric acid,
(166) 4-{3-[(Methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxobutyric acid,
(167) 4-[3-Benzyl-5-(5-hydroxy-pentyl)-phenyl]-2,4-dioxo-butyric acid,
(168) 4-(3-Benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid,
(169) 4-[3-(3-tert-Butoxy-2-hydroxy-propyl)-5-(2-methyl-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(170) 2,4-Dioxo-4-[3-(2,3-dimethoxy-benzyl)-phenyl]-butyric acid,
(171) 4-[3-(Methoxyphenylmethyl)phenyl]-2,4-dioxobutyric acid,
(172) 4-[3-[Hydroxy-(tetrahydro-furan-3-yl)-methyl]-5-(2-methylbenzyl)-phenyl]--2,4-dioxo-butyric acid,
(173) 2,4-Dioxo-4-(3-phenoxymethyl-phenyl)-butyric acid,
(174) 2,4-Dioxo-4-(3-phenoxymethyl-phenyl)-butyric acid
(175) 4-[3-Benzyl-5-(cyclopropylcarboxamido)-phenyl]-2,4-dioxobutyric acid,
(176) 4-[3-Benzyl-5-(t-butoxycarbamoyl)phenyl]-2,4-dioxobutyric acid,
(177) 4-[3-(Hydroxy-phenyl-methyl)-phenyl]-2,4-dioxo-butyric acid,
(178) 4-(5-Benzyl-2,3-dimethylphenyl)-2,4-dioxo-butyric acid,
(179) n-[3-(3,5-Dibromobenzyl)phenyl]-2,4-dioxo-butyric acid,
(180) 4-[3-(2-Methyl-benzyl)-5-pyrimidin-2-yl-phenyl]-2,4-dioxobutyric acid,
(181) 4-[3-Benzyl-2-(pyrimidin-2-ylamino)-phenyl]-2,4-dioxobutyric acid
(182) 4-[3-Benzoimidazol-1-ylmethyl-5-(2-methyl-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(183) 2,4-Dioxo-4-[3-(3-trifluoromethylbenzyl)phenyl]butyric acid,
(184) 4-(4-Phenoxy-phenyl)-2,4-dioxo-butyric acid,
(185) 2,4-Dioxo-4-(3-[1,2,3]triazol-2-ylmethyl-phenyl)-butyric acid,
(186) 4-[3-Benzyl-5-(6-methoxy-pyridin-2-yl)-phenyl]-2,4-dioxobutyric acid,
(187) 4-(3-Benzotriazol-2-ylmethyl-phenyl)-2,4-dioxo-butyric acid,
(188) 4-[3-Benzyl-5-(2-(4-methylpiperazin-1-yl)-pyrazin-6-yl)phenyl]-2,4-dioxobutyric acid,
(189) 4-[4-(3-Phenethyl)phenyl]-2,4-dioxobutyric acid,
(190) 4-[4-(3-Chlorobenzyl)phenyl]-2,4-dioxobutyric acid,
(191) 4-(3-Benzoimidazol-1-ylmethyl-phenyl)-2,4-dioxo-butyric acid,
(192) 4-[3-Benzyloxy-5-(6-tert-butoxycarbonylaminohexyloxy)phenyl]-2-hydroxy-4-oxo-but-2-enoic acid,
(193) 4-(3-Benzotriazol-1-ylmethyl-phenyl)-2,4-dioxo-butyric acid,
(194) 4-[3-(3,5-Dimethyl-pyrazol-1-ylmethyl)-phenyl]-2,4-dioxobutyric acid,
(195) 4-[3-Benzyloxy-5-(2-morpholin-4-yl-ethoxy)phenyl]-2-hydroxy-4-oxo-but-2-enoic acid,
(196) 4-(4-Methyl-3-phenoxy-phenyl)-2,4-dioxo-butyric acid
(197) 4-[3-(2xe2x80x94Hydroxy-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(198) 4-[3-Benzyl-5-(6-dimethylamino-pyrazin-2-yl)-phenyl]-2,4-dioxo-butyric acid, and
(199) 4-(5-Benzyl-2-methoxypyridin-3-yl)-2,4-dioxobutyric acid;
and tautomers and pharmaceutically acceptable salts thereof.
One class of compounds of structural formula (I) includes:
(1) 4-(3-Benzylphenyl)-2,4-dioxobutanoic acid,
(2) 4-[3-(5-methyl-thiophen-2-ylmethyl)-phenyl]-2,4-dioxo-butyric acid,
(3) 4-{3-[(methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxobutyric acid,
(4) 4-(3-benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid,
(5) 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid,
(6) 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid,
(7) 4-[3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid,
(8) 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxobutyric acid,
(9) 4-(5-Benzyl-2-isopropoxyphenyl)-2,4-dioxobutyric acid,
(10) 4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid,
(11) 4-[5-Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid,
(12) 4-(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid,
(13) 4-(5-Benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid,
(14) 4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4-dioxobutyric acid,
(15) 4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxobutyric acid,
(16) 4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric acid,
(17) 4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylphenyl)-2,4-dioxobutyric acid,
(18) 4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid,
(19) 4-[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl) phenyl]-2,4-dioxo-butyric acid,
(20) 4-(5-benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyric acid,
(21) 4-(5-Benzyl-2-isopropoxy-3-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid,
(22) 4-(5-Benzyl-2-isopropoxy-3-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid,
(23) 4-[5-Benzyl-2-(3-N,N-dimethylaminopropoxy)-3-methoxyphenyl]-2,4-dioxobutyric acid,
(24) 4-[3-(Phenyldifluoromethyl)phenyl]-2,4-dioxobutyric acid,
(25) 4-(5-Benzyl-2-cyclopropyloxyphenyl)-2,4-dioxobutyric acid,
(26) 4-[5-Benzyl-2-isopropoxy-3-(1-piperidinylmethyl)phenyl]-2,4-dioxo-butyric acid,
(27) 4-[5-Benzyl-2-(2-dimethylamino-1-methylethoxy)phenyl]-2,4-dioxo-butyric acid,
(28) 4-[5-Benzyl-2-(1-methylpiperidin-4-yloxy)phenyl]-2,4-dioxo-butyric acid,
(29) 4-[3-Benzyl-5-(4-benzylpiperazin-1-yl)phenyl]-2,4-dioxo-butyric acid, and
(30) 4-[5-Benzyl-2-isopropoxy-3-(pyridin-2-ylaminomethyl) phenyl]-2,4-dioxo-butyric acid;
and tautomers and pharmaceutically acceptable salts thereof.
One class of compounds of the present invention is represented by the structural formula below: 
Another class of compounds of the present invention is represented by the structural formula below: 
Another class of compounds of the present invention is represented by the following structural formula: 
Still another class of compounds of the present invention is represented by the formula below: 
Another class of compounds of the present invention is represented by the following structural formula: 
Yet another class of compounds of the present invention is represented by the following structural formula: 
Still another class of compounds of the present invention is represented by the following structural formula: 
Another class of compounds of the present invention is represented by the following structural formula: 
Yet another class of compounds of the present invention is represented by the following structural formula: 
Still another class of compounds of the present invention is represented by the following structural formula: 
Another class of compounds of the present invention is represented by the following structural formula: 
Yet another class of compounds of the present invention is represented by the following structural formula: 
Still another class of compounds of the present invention is represented by the following structural formula: 
Another class of compounds of the present invention is represented by the following structural formula: 
Still another class of compounds of the present invention is represented by the following structural formula: 
One class of compounds of the present invention is represented by the structural formula below: 
Another class of compounds of the present invention is represented by the following structural formula: 
Still another class of compounds of the present invention is represented by the formula below: 
Another class of compounds of the present invention is represented by the following structural formula: 
Another class of compounds of the present invention is represented by the following structural formula: 
Another class of compounds of the present invention is represented by the following structural formula: 
In one embodiment of the present invention, A is selected from:
(1) phenyl,
(2) pyridyl,
(3) naphthyl,
(4) indolyl, provided that the aryl ring is substituted by the dioxobutyric acid/ester moiety in structural formula (I), 
In another embodiment of the present invention, A is selected from:
(1) phenyl,
(2) pyridinyl,
(3) indolyl, provided that 6-membered aromatic ring is substituted by the dioxobutyric moiety in structural formula (I); 
In still another embodiment of the present invention, A is phenyl.
In one embodiment of the present invention, R1 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94C1-5 alkyl,
(3) xe2x80x94C1-6 alkyl-OR7;
(4) xe2x80x94Oxe2x80x94C1-6 alkyl-OR7,
(5) xe2x80x94Oxe2x80x94C1-6 alkyl-SR7,
(6) xe2x80x94CF3 or xe2x80x94CH2CF3,
(7) xe2x80x94F, Cl, or Br,
(8) xe2x80x94NO2,
(9) xe2x80x94C0-3 alkyl-N(R4)(R5),
(10) -phenyl,
(11) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) xe2x80x94CF3,
(f) xe2x80x94OCF3,
(g) xe2x80x94CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94CF3,
(f) xe2x80x94SCH3,
(g) xe2x80x94CN,
(h) hydroxy,
(i) phenyloxy,
(j) xe2x80x94C0-6 alkyl-N(R7)2, 
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(13) xe2x80x94Oxe2x80x94R6,
(14) xe2x80x94Oxe2x80x94C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms,
(15) xe2x80x94Oxe2x80x94C1-6 alkyl-NHxe2x80x94C(O)xe2x80x94OR7;
(16) xe2x80x94Oxe2x80x94C2-6 alkyl-N(R4)(R5);
(17) xe2x80x94Sxe2x80x94C1-3 alkyl;
(18) xe2x80x94C(O)CH2C(O)C(O)OR7;
(19) xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94Oxe2x80x94R7; and
(20) xe2x80x94C(OH)(CH3)xe2x80x94CH2N(R4)(R5).
In another embodiment of the present invention, R1 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94CH3,
(3) xe2x80x94C1-6 alkyl-OR7;
(4) xe2x80x94Oxe2x80x94C1-6 alkyl-OR7,
(5) xe2x80x94Oxe2x80x94C1-6 alkyl-SR7,
(6) xe2x80x94CF3 or xe2x80x94CH2CF3,
(7) xe2x80x94Cl,
(8) xe2x80x94F,
(9) xe2x80x94C0-3 alkyl-N(R4)(R5),
(10) -phenyl,
(11) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) xe2x80x94F, xe2x80x94Cl, or xe2x80x94Br,
(b) CH3,
(c) xe2x80x94OCH3, OCH2CH3, OCF3, or OCH2CF3,
(d) xe2x80x94CF3,
(e) xe2x80x94SCH3,
(f) xe2x80x94CN,
(g) hydroxy,
(h) xe2x80x94C0-6 alkyl-N(R7)2,
(12) xe2x80x94Oxe2x80x94CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) xe2x80x94F, xe2x80x94Cl, or xe2x80x94Br,
(b) xe2x80x94CH3,
(c) xe2x80x94OCH3, OCH2CH3, OCF3, or OCH2CF3,
(d) xe2x80x94CF3,
(e) xe2x80x94SCH3,
(f) xe2x80x94CN,
(g) hydroxy,
(h) xe2x80x94C0-6 alkyl-N(R7)2,
(13) xe2x80x94Oxe2x80x94C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, and
(14) xe2x80x94C(O)CH2C(O)C(O)OH;
(15) xe2x80x94Oxe2x80x94C1-6 alkyl-NHxe2x80x94C(O)xe2x80x94OR7;
(16) xe2x80x94Oxe2x80x94CH2CH2 N(CH3)2,
(17) xe2x80x94Oxe2x80x94CH(CH3)CH2N(CH3)2,
(18) xe2x80x94Oxe2x80x94CH2CH2 NH2,
(19) xe2x80x94Oxe2x80x94CH(CH3)CH2NH2,
(20) xe2x80x94Sxe2x80x94CH3,
(21) xe2x80x94C(O)CH2C(O)C(O)OH,
(22) xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94Oxe2x80x94R7, and
(23) xe2x80x94C(OH)(CH3)xe2x80x94CH2N(R4)(R5).
In yet another embodiment of the present invention, R1 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94CH3,
(3) xe2x80x94CH2OCH3,
(4) xe2x80x94OCH2CH2OH,
(5) xe2x80x94OCH2CH2OCH3,
(6) xe2x80x94(CH2)6xe2x80x94OH,
(7) xe2x80x94CF3,
(8) xe2x80x94F,
(9) xe2x80x94Cl,
(10) xe2x80x94C0-3 alkyl-N(R4)(R5),
(11) -phenyl,
(12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) xe2x80x94F, xe2x80x94Cl, or xe2x80x94Br,
(b) CH3,
(c) xe2x80x94OCH3, OCH2CH3, OCF3, or OCH2CF3,
(d) xe2x80x94CF3,
(e) xe2x80x94CN,
(f) hydroxy,
(g) xe2x80x94C0-6 alkyl-N(R7)2,
(13) xe2x80x94Oxe2x80x94CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) xe2x80x94F, xe2x80x94Cl, or xe2x80x94Br,
(b) xe2x80x94CH3,
(c) xe2x80x94OCH3, OCH2CH3, OCF3, or OCH2CF3,
(d) xe2x80x94CF3,
(e) xe2x80x94CN,
(f) hydroxy,
(g) xe2x80x94C0-6 alkyl-N(R7)2,
(14) xe2x80x94Oxe2x80x94CH3,
(15) xe2x80x94OCH2CH3,
(16) xe2x80x94OCH2CF3,
(17) xe2x80x94OCF3,
(18) xe2x80x94OCH(CH3)2,
(19) xe2x80x94C(O)CH2C(O)C(O)OH,
(20) xe2x80x94Oxe2x80x94C1-6 alkyl-NHxe2x80x94C(O)xe2x80x94OR7,
(21) xe2x80x94Oxe2x80x94CH2CH2N(CH3)2,
(22) xe2x80x94Oxe2x80x94CH(CH3)CH2N(CH3)2,
(23) xe2x80x94Oxe2x80x94CH2CH2 NH2,
(24) xe2x80x94Oxe2x80x94CH(CH3)CH2NH2,
(25) xe2x80x94Sxe2x80x94CH3,
(26) xe2x80x94C(O)CH2C(O)C(O)OH,
(27) xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94Oxe2x80x94R7, and
(28) xe2x80x94C(OH)(CH3)xe2x80x94CH2N(R4)(R5).
In another embodiment of the present invention, R1 is selected from:
(1) xe2x80x94H,
(2) -phenyl,
(3) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo, selected from xe2x80x94F, xe2x80x94Br, xe2x80x94Cl,
(b) methyl, and
(c) methoxy,
(4) phenyl C1-3 alkyl-,
(5) xe2x80x94Oxe2x80x94R6,
(6) xe2x80x94Oxe2x80x94CH3, and
(7) xe2x80x94C(O)CH2C(O)C(O)OR7.
In one embodiment of the present invention, R2 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94R3,
(3) xe2x80x94C1-6 alkyl,
(4) xe2x80x94C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom,
(5) xe2x80x94Oxe2x80x94R6,
(6) xe2x80x94Sxe2x80x94R6,
(7) xe2x80x94Oxe2x80x94C1-6 alkyl-SR6;
(8) xe2x80x94C1-6 alkyl (OR6)(R4),
(9) xe2x80x94C0-6 alkyl-N(R4)(R6),
(10) xe2x80x94C1-6 alkyl-Sxe2x80x94R6,
(11) xe2x80x94C0-6 alkyl-C(O)xe2x80x94R6,
(12) xe2x80x94C0-6 alkyl-C(O)CH2xe2x80x94C(O)xe2x80x94OH,
(13) xe2x80x94C1-6 alkyl NR4C(O)xe2x80x94R6,
(14) xe2x80x94C1-6 alkyl-C(O)N(R4)(R5), and
(15) xe2x80x94CH2(OR7)xe2x80x94R6.
In another embodiment of the present invention, R2 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94R3,
(3) xe2x80x94CH3,
(4) xe2x80x94C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom,
(5) xe2x80x94Oxe2x80x94R6,
(6) xe2x80x94Sxe2x80x94R6,
(7) xe2x80x94Oxe2x80x94C1-6 alkyl-SR6;
(8) xe2x80x94C1-6 alkyl (OR6)(R4),
(9) xe2x80x94C0-6 alkyl-N(R4)(R6),
(10) xe2x80x94C0-6 alkyl C(O)xe2x80x94R6,
(11) xe2x80x94C0-6 alkyl C(O)CH2xe2x80x94C(O)xe2x80x94OH,
(12) xe2x80x94C1-6 alkyl NR4C(O)xe2x80x94R6,
(13) xe2x80x94C1-6 alkyl-C(O)N(R4)(R5), and
(14) xe2x80x94CH2(OR7)xe2x80x94R6.
In yet another embodiment of the present invention, R2 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94R3,
(3) xe2x80x94CH2xe2x80x94R3,
(4) xe2x80x94CH2CH2xe2x80x94R3,
(5) xe2x80x94CF2xe2x80x94R3,
(6) xe2x80x94CH(CH3)xe2x80x94R3,
(7) xe2x80x94Oxe2x80x94R6,
(8) xe2x80x94S-phenyl,
(9) xe2x80x94C1-6 alkyl (OR6)(R4),
(10) xe2x80x94C0-6 alkyl-N(R4)(R6),
(11) xe2x80x94C(O)xe2x80x94R3,
(12) xe2x80x94C0-6 alkyl C(O)CH2xe2x80x94C(O)xe2x80x94OH,
(13) xe2x80x94C1-6 alkyl NR4C(O)xe2x80x94R6,
(14) xe2x80x94CH(OCH3)R3, and
(15) xe2x80x94CH(OH)R3.
In another embodiment of the present invention, R2 is selected from:
(1) xe2x80x94R3,
(2) xe2x80x94C1-6 alkyl substituted with R3,
(3) xe2x80x94Oxe2x80x94R6,
(4) xe2x80x94S(O)nxe2x80x94R6,
(5) xe2x80x94C1-6 alkyl (OR6)(R4),
(6) xe2x80x94C0-6 alkyl-N(R4)(R6), and
(7) xe2x80x94C1-6 alkyl-C(O)N(R4)(R5).
In one embodiment of the present invention, R3 is selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94Sxe2x80x94C1-6 alkyl,
(f) xe2x80x94CN,
(g) hydroxy,
(h) phenyloxy,
(i) xe2x80x94C0-6 alkyl-N(R7)2, 
(k) oxo, and
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(3) thienyl,
(4) substituted thienyl substituted on carbon with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94Sxe2x80x94C1-6 alkyl,
(f) xe2x80x94CN,
(g) hydroxy,
(h) phenyloxy,
(i) xe2x80x94C0-6 alkyl-N(R7)2, 
(k) oxo, and
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(5) pyridyl,
(6) substituted pyridyl substituted on carbon with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94Sxe2x80x94C1-6 alkyl,
(f) xe2x80x94CN,
(g) hydroxy,
(h) phenyloxy,
(i) xe2x80x94C0-6 alkyl-N(R7)2, 
(k) oxo, and
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(7) imidazolyl,
(8) substituted imidazolyl substituted on carbon with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94Sxe2x80x94C1-6 alkyl,
(f) xe2x80x94CN,
(g) hydroxy,
(h) phenyloxy,
(i) xe2x80x94C0-6 alkyl-N(R7)2, 
(k) oxo, and
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(9) pyrrolyl,
(10) substituted pyrrolyl substituted on carbon with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94Sxe2x80x94C1-6 alkyl,
(f) xe2x80x94CN,
(g) hydroxy,
(h) phenyloxy,
(i) xe2x80x94C0-6 alkyl-N(R7)2, 
(k) oxo, and
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(11) pyrazolyl,
(12) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94Sxe2x80x94C1-6 alkyl,
(f) xe2x80x94CN,
(g) hydroxy,
(h) phenyloxy,
(i) xe2x80x94C0-6 alkyl-N(R7)2, 
(k) oxo, and
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(15) piperidinyl,
(16) substituted piperidinyl substituted on carbon with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1 6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O,
(h) benzyl, and
(i) hydroxy;
(17) morpholinyl,
(18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O,
(h) benzyl, and
(i) hydroxy;
(19) hexahydrothieno[3,4-d]imidazolyl,
(20) substituted hexahydrothieno[3,4-d]substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents independently selected from:
(a) oxo,
(b) halogen,
(c) C1-6 alkyl,
(d) C1-6 alkyloxy-,
(e) xe2x80x94CF3,
(f) xe2x80x94OCF3,
(g) xe2x80x94CN, and
(h) hydroxy,
(21) naphthyl,
(22) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) -halogen,
(b) xe2x80x94C1-6 alkyl,
(C) xe2x80x94C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN, and
(g) -hydroxy,
(23) indolyl,
(24) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) -halogen,
(b) xe2x80x94C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN, and
(g) -hydroxy;
(25) C3-6 cycloalkyl fused with a phenyl ring;
(26) substituted C3-6 cycloalkyl fused with a phenyl ring substituted on carbon with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O, and
(h) hydroxy;
(27) pyrazinyl;
(28) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94Sxe2x80x94C1-6 alkyl,
(f) xe2x80x94CN,
(g) hydroxy,
(h) phenyloxy,
(i) xe2x80x94C0-6 alkyl-N(R7)2, 
(k) oxo, and
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(29) pyrimidinyl;
(30) substituted pyrimidinyl substituted on nitrogen or carbon with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94Sxe2x80x94C1-6 alkyl,
(f) xe2x80x94CN,
(g) hydroxy,
(h) phenyloxy,
(i) xe2x80x94C0-6 alkyl-N(R7)2, 
(k) oxo, and
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(31) triazolyl;
(32) substituted triazolyl with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94Sxe2x80x94C1-6 alkyl,
(f) xe2x80x94CN,
(g) hydroxy,
(h) phenyloxy,
(i) xe2x80x94C0-6 alkyl-N(R7)2, 
(k) oxo, and
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(33) tetrazolyl;
(34) substituted tetrazolyl with a substituent selected from:
(a) halogen,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) phenyl,
(e) xe2x80x94Sxe2x80x94C1-6 alkyl,
(f) xe2x80x94CN,
(g) hydroxy,
(h) phenyloxy,
(i) xe2x80x94C0-6 alkyl-N(R7)2, 
(k) oxo, and
(l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) xe2x80x94CF3, and
(iv) hydroxy;
(35) C3-6 cycloalkyl;
(36) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O,
(h) benzyl, and
(i) hydroxy;
(37) tetrahydrofuran;
(38) substituted tetrahydrofuran substituted with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O,
(h) benzyl, and
(i) hydroxy;
(39) piperazinyl;
(40) substituted piperazinyl substituted with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O,
(h) benzyl, and
(i) hydroxy;
(41) benzotriazolyl,
(42) substituted benzotriazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) -halogen,
(b) xe2x80x94C1-6 alkyl,
(c) xe2x80x94C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN, and
(g) -hydroxy;
(43) benzoimidazolyl,
(44) substituted benzoimidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) -halogen,
(b) xe2x80x94C1-6 alkyl,
(c) xe2x80x94C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN, and
(g) -hydroxy.
In another embodiment of the present invention, R3 is selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, xe2x80x94Br,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) xe2x80x94CN,
(e) hydroxy, and
(f) oxo;
(3) thienyl,
(4) substituted thienyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from F, Cl, and Br,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, and
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom;
(5) pyridyl,
(6) substituted pyridyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br;
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) hydroxy, and
(e) oxo;
(7) imidazolyl,
(8) pyrrolyl,
(9) pyrazolyl
(10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br;
(b) xe2x80x94CH3,
(c) xe2x80x94CF3,
(d) xe2x80x94OCH3,
(e) xe2x80x94OCF3, and
(f) hydroxy;
(11) C3-6 cycloalkyl,
(12) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) CH3,
(c) methyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O, and
(h) hydroxy;
(13) piperidinyl,
(14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from:
(a) halogen selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) methyl,
(c) methoxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x95x90O, and
(g) hydroxy;
(15) morpholinyl,
(16) substituted morpholinyl substituted on carbon or nitrogen with 1 or 2 substituents independently selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) methyl,
(c) methoxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3, and
(f) hydroxy,
(17) hexahydrothieno[3,4-d]imidazolyl,
(18) naphthyl,
(19) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) -halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) methyl,
(c) methoxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN, and
(g) -hydroxy,
(20) indolyl,
(21) 1,2,3,4-tetrahydronaphthalenyl,
(22) substituted 1,2,3,4-tetrahydronaphthalenyl substituted on carbon with a substituent selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) methyl,
(c) methoxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) xe2x80x94CN,
(g) xe2x95x90O, and
(h) hydroxy;
(23) pyrazinyl;
(24) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,
(d) hydroxy,
(e) phenyloxy,
(f) xe2x80x94C0-6 alkyl-N(R7)2, and 
(25) pyrimidinyl;
(26) substituted pyrimidinyl substituted on nitrogen or carbon with a substituent selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) methyl,
(c) methoxy-, and
(d) phenyl,
(27) triazolyl;
(28) substituted triazolyl with a substituent selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) methyl,
(c) methoxy-, and
(d) hydroxy,
(29) tetrazolyl;
(30) substituted tetrazolyl with a substituent selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) methyl,
(c) methoxy-, and
(d) hydroxy,
(31) C3-6 cycloalkyl;
(32) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) methyl,
(c) methoxy-,
(d) xe2x80x94CF3, and
(e) xe2x80x94OCF3,
(33) tetrahydrofuran;
(34) substituted tetrahydrofuran substituted with one or two substituents independently selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) methyl,
(c) methoxy-,
(d) xe2x80x94CF3, and
(e) xe2x80x94OCF3,
(35) piperazinyl;
(36) substituted piperazinyl substituted with one or two substituents independently selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) xe2x80x94CF3,
(e) xe2x80x94OCF3,
(f) benzyl, and
(g) hydroxy;
(37) benzotriazolyl,
(38) substituted benzotriazolyl substituted on carbon with one or two substituents independently selected from:
(a) -halogen, selected from xe2x80x94F, xe2x80x94Cl. and xe2x80x94Br,
(b) -methyl,
(c) methoxy-,
(d) xe2x80x94CF3, and
(e) xe2x80x94OCF3,
(39) benzoimidazolyl, and
(40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from:
(a) -halogen, selected from xe2x80x94F, xe2x80x94Cl. and xe2x80x94Br,
(b) -methyl,
(c) methoxy-,
(d) xe2x80x94CF3, and
(e) xe2x80x94OCF3.
In yet another embodiment of the present invention, each R3 is independently selected from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, xe2x80x94Br,
(b) xe2x80x94CH3,
(c) methyloxy-,
(d) ethyloxy-,
(e) xe2x80x94OCH2CF3,
(f) xe2x80x94OCF2CH3,
(g) xe2x80x94CF3,
(h) xe2x80x94CH2CF3,
(i) xe2x80x94CF2CH3,
(j) xe2x80x94OCF3,
(k) xe2x80x94CN, and
(l) hydroxy;
(3) thienyl,
(4) substituted thienyl substituted on a carbon atom with a substituent selected from:
(a) F,
(b) Cl, and
(c) methyl;
(5) pyridyl,
(6) substituted pyridyl substituted on a carbon with a substituent selected from:
(a) xe2x80x94F,
(b) xe2x80x94Cl,
(c) xe2x80x94CH3,
(d) xe2x80x94CF3,
(e) xe2x80x94OCH3,
(f) xe2x80x94OCF3,
(g) hydroxy, and
(h) oxo;
(7) pyrazolyl
(8) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) xe2x80x94F,
(b) xe2x80x94Cl,
(c) xe2x80x94CH3, and
(d) xe2x80x94CF3;
(9) C3-6 cycloalkyl,
(10) piperidinyl,
(11) substituted piperidinyl substituted on carbon with a substituent selected from:
(a) methoxy-,
(b) xe2x80x94OCF3,
(c) xe2x95x90O, and
(d) hydroxy;
(12) morpholinyl,
(13) naphthyl,
(14) 1,2,3,4-tetrahydronaphthalenyl,
(15) pyrazinyl;
(16) substituted pyrazinyl substituted on nitrogen or carbon with a substituent selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, and xe2x80x94Br,
(b) methyl,
(c) xe2x80x94CF3,
(d) methoxy-,
(e) xe2x80x94N(CH3)2, and 
(17) pyrimidinyl,
(18) [1,2,3]-triazolyl,
(19) [1,2,4]-triazolyl,
(20) tetrazolyl;
(21) cyclopropyl,
(22) cyclobutyl,
(23) cyclopentyl,
(24) cyclohexyl,
(25) tetrahydrofuran,
(26) piperazinyl;
(27) substituted piperazinyl substituted with a substituent selected from:
(a) xe2x80x94F,
(b) xe2x80x94Cl,
(c) methyl,
(d) xe2x80x94CF3, and
(e) benzyl,
(28) benzotriazolyl, and
(29) benzoimidazolyl.
In still another embodiment of the present invention, R3 is selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, selected from xe2x80x94F, xe2x80x94Cl, xe2x80x94Br,
(b) xe2x80x94CH3,
(c) methyloxy-,
(d) phenyl,
(e) xe2x80x94CF3,
(f) xe2x80x94OCF3,
(g) xe2x80x94CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, selected from xe2x80x94F, xe2x80x94Cl, xe2x80x94Br,
(ii) xe2x80x94CH3,
(iii) xe2x80x94CF3, and
(iv) hydroxy.
In one embodiment of the present invention, each R4 is independently selected from:
(1) xe2x80x94H,
(2) xe2x80x94C1-4 alkyl,
(3) xe2x80x94CF3,
(4) xe2x80x94R3,
(5) xe2x80x94C2-3 alkenyl,
(6) xe2x80x94C1-3 alkyl-R3,
(7) xe2x80x94C2-3 alkenyl-R3, and
(8) xe2x80x94C(O)xe2x80x94R3.
In another embodiment of the present invention, each R4 is independently selected from:
(1) xe2x80x94H,
(2) xe2x80x94C1-4 alkyl,
(3) xe2x80x94CF3,
(4) xe2x80x94R3,
(5) xe2x80x94C1-3 alkyl-R3, and
(6) xe2x80x94C(O)xe2x80x94R3.
In one embodiment of the present invention, each R5 is independently selected from:
(1) xe2x80x94H,
(2) xe2x80x94C1-3 alkyl,
(3) xe2x80x94CF3,
(4) xe2x80x94R3,
(5) xe2x80x94C2-3 alkenyl,
(6) xe2x80x94C1-3 alkyl-R3,
(7) xe2x80x94S(O)nxe2x80x94R3,
(8) xe2x80x94C(O)xe2x80x94R3,
(9) xe2x80x94C(O)OR4, and
(10) xe2x80x94C(O)C(O)OH;
In another embodiment of the present invention, each R5 is independently selected from:
(1) xe2x80x94H,
(2) xe2x80x94C1-3 alkyl,
(3) xe2x80x94CF3,
(4) xe2x80x94R3,
(5) xe2x80x94C1-3 alkyl-R3,
(6) xe2x80x94C(O)xe2x80x94R3,
(7) xe2x80x94C(O)OR4, and
(8) xe2x80x94C(O)C(O)OH.
In another embodiment of the present invention, each R5 is independently selected from:
(1) xe2x80x94H,
(2) xe2x80x94CH3,
(3) xe2x80x94CF3,
(4) phenyl,
(5) -benzyl,
(6) xe2x80x94C(O)OR4, and
(7) xe2x80x94C(O)C(O)OH;
In one embodiment of the present invention, R7 is independently selected from H, and xe2x80x94C1-6 alkyl.
In one embodiment of the present invention, R8 is selected from hydrogen, methyl and xe2x80x94Oxe2x80x94C1-6 alkyl.
In yet another embodiment of the present invention, R8 is hydrogen.
In one embodiment of the present invention, R9 is selected from:
(1) xe2x80x94H,
(2) xe2x80x94Oxe2x80x94C1-3 alkyl,
(3) xe2x80x94OH, and
(4) oxo.
Also included within the present invention are pharmaceutical compositions useful for inhibiting HIV integrase, comprising an effective amount of a compound of this invention, and a pharmaceutically acceptable carrier. Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC, are also encompassed by the present invention, as well as a method of inhibiting HIV integrase, and a method of treating infection by HIV, or of treating AIDS or ARC. Additionally, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an AIDS treatment agent selected from:
(1) an AIDS antiviral agent,
(2) an anti-infective agent, and
(3) an immunomodulator.
The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
As is recognized by one of ordinary skill in the art, the diketo-acid/ester compounds of the present invention exist as tautomers, and thus by using the phrase xe2x80x9cand tautomers thereofxe2x80x9d in describing compounds of structural formula (I), Applicants also intend the following tautomeric forms of the same compound (IA) and (IB): 
By naming or referring to compound (I) and tautomers thereof, it is understood for the purposes of the present application that the tautomers (IA) and (IB) are also intended. Similarly, by referring to compound (IA), it is understood for the purposes of the present application that the tautomers (I) and (IB) are also intended. The same holds true for references to tautomer (IB).
When any variable (e.g., R3, R4, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The compounds of the present inventions are useful in the inhibition of HIV integrase, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.
The present invention also provides for the use of a compound of structural formula (I) to make a pharmaceutical composition useful for inhibiting HIV integrase and in the treatment of AIDS or ARC.
Schemes AI, AII, and AVI illustrate the preparation of compounds wherein A is di-aryloxy/alkyloxy substituted phenyl. Scheme AIII illustrates the preparation of the compounds of the present invention wherein A is arylalkyl substituted phenyl. Schemes AIV and AV describe the synthesis of compounds wherein A is amino substituted phenyl. Scheme AVII describes the synthesis of compounds wherein A is indolyl. Scheme IX illustrates the synthesis of pyridyl compounds. 
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form.
Also, in the case of an acid (xe2x80x94COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
The terms xe2x80x9cadministration ofxe2x80x9d and or xe2x80x9cadministering axe2x80x9d compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays, sterile injectible preparations, for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.
When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
The injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
The compounds of this invention can be administered orally to humans in a dosage range of 1 to 1000 mg/kg body weight in divided doses. One preferred dosage range is 0.1 to 200 mg/kg body weight orally in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg body weight orally in divided doses. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the HIV integrase inhibitor compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, imunomodulators, antiinfectives, or vaccines, such as those in the following table.
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-Nxe2x80x2-(t-butylcarboxamido)piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. Pat. No. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz. The preparation of ddC, ddI and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-Nxe2x80x2-(t-butylcarboxamido)-piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. Pat. No. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day.
The following examples are provided to further illustrate details for the preparation and use of the compounds of the present invention. The examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed. Furthermore, the compounds described in the following examples are not to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless noted otherwise.
Abbreviations: Ac represents acetyl; ACN is acetonitrile; Bn represents benzyl; Bu represents butyl; Calc""d represents calculated; DEAD is diethylazido-carboxylate; DME is dimethoxyethane; DMF is dimethyl formamide; DMSO is dimethylsulfoxide; EI represents electron impact; ES represents electrospray; Et represents ethyl; FAB represents fast atom bombardment; IPA is isopropyl alcohol; LDA is lithium diisopropylamide; L-Selectride(copyright) is lithium tri-sec-butylborohydride; MEK is methyl ethyl ketone; Me represents methyl; NMP is 1-methyl-2-pyrrolidinone; PDA is photodiode array; rt and RT represent room temperature; THF is tetrahydrofuran; TLC is thin layer (SiO2) chromatography.